Michel Komajda1, Richard Isnard1, Alain Cohen-Solal2, Marco Metra3, Burkert Pieske4, Piotr Ponikowski5, Adriaan A Voors6, Fabienne Dominjon7, Cécile Henon-Goburdhun7, Matthieu Pannaux8, Michael Böhm9. 1. Department of Cardiology, University of Pierre and Marie Curie Paris VI, La Pitié-Salpêtrière Hospital, Paris, France. 2. UMR-S 942, Department of Cardiology, Paris Diderot University, Sorbonne Paris Centre, Lariboisière Hospital, Paris, France. 3. Department of Cardiology, University of Brescia, Brescia, Italy. 4. Department of Cardiology, Charité University, Berlin, Germany. 5. Department of Heart Diseases, Medical University and Centre for Heart Diseases, Military Hospital, Wrocław, Poland. 6. Department of Cardiology, University of Groningen, Groningen, the Netherlands. 7. Department of Cardiovascular Development, Institut de Recherches Internationales Servier (IRIS), Suresnes, France. 8. Department of Methodology and Data Valorisation, Institut de Recherches Internationales Servier (IRIS), Suresnes, France. 9. Department of Cardiology, Universitätskliniken des Saarlandes, Klinikum für Innere Medizin III, Homburg/Saar, Germany.
Abstract
AIMS: This randomized, double-blind, placebo-controlled trial assessed whether heart rate (HR) reduction with ivabradine improves cardiac function in heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: The prEserveD left ventricular ejectIon fraction chronic heart Failure with ivabradine studY (EDIFY) included 179 patients in New York Heart Association (NYHA) classes II and III, in sinus rhythm, with HR of ≥70 b.p.m., NT-proBNP of ≥220 pg/mL (BNP ≥80 pg/mL) and left ventricular ejection fraction of ≥45%. Ivabradine (or placebo) was titrated to 7.5 mg b.i.d. Patients were followed for 8 months on the change and assessed for three co-primary endpoints: echo-Doppler E/e' ratio, distance on the 6-min walking test (6MWT), and plasma NT-proBNP concentration. At baseline, median E/e' was 12.8 [interquartile range (IQR): 9.9-16.3], median distance on the 6MWT was 320 m (IQR: 247-375 m), and median NT-proBNP was 375 pg/mL (IQR: 253-701 pg/mL). Baseline median HR was 75 b.p.m. (IQR: 70-107 b.p.m.). A total of 171 patients (87 in the ivabradine group, 84 in theplacebo group) were evaluated for treatment efficacy. After 8 months of treatment, findings showed a median change in HR of -13.0 b.p.m. (IQR: -18.0 to -6.0 b.p.m.) in the ivabradine group and -3.5 b.p.m. (IQR: -11.5 to 3.0 b.p.m.) in the placebo group [estimated between-group difference: 7.7 b.p.m.; 90% confidence interval (CI) -10 to -5.4; P < 0.0001]. No evidence of improvement was found in any of the three co-primary endpoints. There was almost no change in median E/e' in either of the two groups [median change: +1.0 (IQR: -0.8 to 2.9) in the ivabradine group; -0.6 (IQR: -2.2 to 1.4) in the placebo group; estimated between-group difference: 1.4, 90% CI 0.3-2.5; P = 0.135]. There were no meaningful changes in the other co-primary endpoints and no apparent trends. There was no significant safety concern. CONCLUSIONS: In patients with HFpEF, HR reduction with ivabradine did not improve outcomes. These findings do not support the use of ivabradine in HFpEF.
RCT Entities:
AIMS: This randomized, double-blind, placebo-controlled trial assessed whether heart rate (HR) reduction with ivabradine improves cardiac function in heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: The prEserveD left ventricular ejectIon fraction chronic heart Failure with ivabradine studY (EDIFY) included 179 patients in New York Heart Association (NYHA) classes II and III, in sinus rhythm, with HR of ≥70 b.p.m., NT-proBNP of ≥220 pg/mL (BNP ≥80 pg/mL) and left ventricular ejection fraction of ≥45%. Ivabradine (or placebo) was titrated to 7.5 mg b.i.d. Patients were followed for 8 months on the change and assessed for three co-primary endpoints: echo-Doppler E/e' ratio, distance on the 6-min walking test (6MWT), and plasma NT-proBNP concentration. At baseline, median E/e' was 12.8 [interquartile range (IQR): 9.9-16.3], median distance on the 6MWT was 320 m (IQR: 247-375 m), and median NT-proBNP was 375 pg/mL (IQR: 253-701 pg/mL). Baseline median HR was 75 b.p.m. (IQR: 70-107 b.p.m.). A total of 171 patients (87 in the ivabradine group, 84 in the placebo group) were evaluated for treatment efficacy. After 8 months of treatment, findings showed a median change in HR of -13.0 b.p.m. (IQR: -18.0 to -6.0 b.p.m.) in the ivabradine group and -3.5 b.p.m. (IQR: -11.5 to 3.0 b.p.m.) in the placebo group [estimated between-group difference: 7.7 b.p.m.; 90% confidence interval (CI) -10 to -5.4; P < 0.0001]. No evidence of improvement was found in any of the three co-primary endpoints. There was almost no change in median E/e' in either of the two groups [median change: +1.0 (IQR: -0.8 to 2.9) in the ivabradine group; -0.6 (IQR: -2.2 to 1.4) in the placebo group; estimated between-group difference: 1.4, 90% CI 0.3-2.5; P = 0.135]. There were no meaningful changes in the other co-primary endpoints and no apparent trends. There was no significant safety concern. CONCLUSIONS: In patients with HFpEF, HR reduction with ivabradine did not improve outcomes. These findings do not support the use of ivabradine in HFpEF.